This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abe, J. Articles by Takuwa, Y. Search for Related Content PubMed PubMed Citation Articles by Abe, J. Articles by Takuwa, Y.

A Fumagillin Derivative Angiogenesis Inhibitor, AGM-1470, Inhibits Activation of Cyclin-dependent Kinases and Phosphorylation of Retinoblastoma Gene Product but not Protein Tyrosyl Phosphorylation or Protooncogene Expression in Vascular Endothelial Cells¹

Departments of Cardiovascular Biology [J. A., W. Z., Y. T.], Physiology [W. Z., N. T., M. K.], and Internal Medicine [J. A., J. T., K. K.], Faculty of Medicine, University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113, Japan

Fumagillin analogue AGM-1470 potently inhibits angiogenesis with a minimal toxicity in vivo and is expected to be of therapeutic use as a powerful antitumor agent (Ingber et al., Nature, 348: 555–557, 1990). In the present study, we have investigated the effects and the mechanism of action of AGM-1470 on cultured human umbilical vein endothelial cells. AGM-1470 acts directly on endothelial cells to inhibit growth factor-induced DNA synthesis, with half maximal and maximal effects obtained at approximately 2 x 10^-10 and 5 x 10^-9 M, respectively. AGM-1470 does not inhibit early G₁ mitogenic events, such as cellular protein tyrosyl phosphorylation or the expression of immediate early genes c-fos and c-myc, but potently inhibits phosphorylation of RB protein, a tumor suppressor retinoblastoma gene product. The later addition of AGM-1470 up to 3 h after the growth factor stimulation still exerts full inhibitory effects on both DNA synthesis and RB phosphorylation, suggesting that the major site of action of AGM-1470 is located relatively late in the G₁ phase. AGM-1470 inhibits growth factor-induced activation of candidate RB kinases cdc2 and cdk2 but fails to inhibit them directly in vitro. AGM-1470 completely abolishes the growth factor-induced mRNA expression of cdc2 and cyclin A and partially inhibits that of cyclin E but has little effect on the mRNA level of cdk2, cdk4, or cyclin D1. These results indicate that angioinhibitory action of AGM-1470 involves suppression of mRNA expression of specific members of cdks and cyclins and of activation of both cdc2 and cdk2 kinases in endothelial cells.

¹ This work was supported by grants from the Ministry of Science and Education in Japan and the Tsumura Foundation for Cardiovascular Research.

² Contributed equally to this manuscript.

³ To whom requests for reprints should be addressed.

Received 1/12/94. Accepted 4/28/94.

This article has been cited by other articles:

				D. Kass, R. S. Bridges, A. Borczuk, and S. Greenberg Methionine Aminopeptidase-2 as a Selective Target of Myofibroblasts in Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 193 - 201. [Abstract] [Full Text] [PDF]

				Y. M. Kim, J. J. An, Y.-J. Jin, Y. Rhee, B. S. Cha, H. C. Lee, and S.-K. Lim Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732 J. Mol. Endocrinol., April 1, 2007; 38(4): 455 - 465. [Abstract] [Full Text] [PDF]

				A. C. Cooper, R. M. Karp, E. J. Clark, N. R. Taghizadeh, J. G. Hoyt, M. T. Labenski, M. J. Murray, G. Hannig, W. F. Westlin, and C. D. Thompson A Novel Methionine Aminopeptidase-2 Inhibitor, PPI-2458, Inhibits Non-Hodgkin's Lymphoma Cell Proliferation In vitro and In vivo Clin. Cancer Res., April 15, 2006; 12(8): 2583 - 2590. [Abstract] [Full Text] [PDF]

				X. Chang, J. C. Tou, C. Hong, H.-A. Kim, J. E. Riby, G. L. Firestone, and L. F. Bjeldanes 3,3'-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice Carcinogenesis, April 1, 2005; 26(4): 771 - 778. [Abstract] [Full Text] [PDF]

				S. Ross, C. Giglione, M. Pierre, C. Espagne, and T. Meinnel Functional and Developmental Impact of Cytosolic Protein N-Terminal Methionine Excision in Arabidopsis Plant Physiology, February 1, 2005; 137(2): 623 - 637. [Abstract] [Full Text] [PDF]

				S. G. Bernier, D. D. Lazarus, E. Clark, B. Doyle, M. T. Labenski, C. D. Thompson, W. F. Westlin, and G. Hannig A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis PNAS, July 20, 2004; 101(29): 10768 - 10773. [Abstract] [Full Text] [PDF]

				P. Selvakumar, A. Lakshmikuttyamma, R. Kanthan, S. C. Kanthan, J. R. Dimmock, and R. K. Sharma High Expression of Methionine Aminopeptidase 2 in Human Colorectal Adenocarcinomas Clin. Cancer Res., April 15, 2004; 10(8): 2771 - 2775. [Abstract] [Full Text] [PDF]

				M. Muramaki, H. Miyake, I. Hara, and S. Kamidono Introduction of Midkine Gene into Human Bladder Cancer Cells Enhances Their Malignant Phenotype But Increases Their Sensitivity to Antiangiogenic Therapy Clin. Cancer Res., November 1, 2003; 9(14): 5152 - 5160. [Abstract] [Full Text] [PDF]

				W. Che, J.-i. Abe, M. Yoshizumi, Q. Huang, M. Glassman, S. Ohta, M. G. Melaragno, V. Poppa, C. Yan, N. Lerner-Marmarosh, et al. p160 Bcr Mediates Platelet-Derived Growth Factor Activation of Extracellular Signal-Regulated Kinase in Vascular Smooth Muscle Cells Circulation, September 18, 2001; 104(12): 1399 - 1406. [Abstract] [Full Text] [PDF]

				J.-R. J. Yeh, R. Mohan, and C. M. Crews The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest PNAS, November 7, 2000; 97(23): 12782 - 12787. [Abstract] [Full Text] [PDF]

				Y. Zhang, E. C. Griffith, J. Sage, T. Jacks, and J. O. Liu Cell cycle inhibition by the anti-angiogenic agent TNP-470 is mediated by p53 and p21WAF1/CIP1 PNAS, June 6, 2000; 97(12): 6427 - 6432. [Abstract] [Full Text] [PDF]

				M. E. Cardenas, M. C. Cruz, M. Del Poeta, N. Chung, J. R. Perfect, and J. Heitman Antifungal Activities of Antineoplastic Agents: Saccharomyces cerevisiae as a Model System To Study Drug Action Clin. Microbiol. Rev., October 1, 1999; 12(4): 583 - 611. [Abstract] [Full Text] [PDF]

				H.M. Fraser, S.E. Dickson, K.D. Morris, G.F. Erickson, and S.F. Lunn The effect of the angiogenesis inhibitor TNP-470 on luteal establishment and function in the primate Hum. Reprod., August 1, 1999; 14(8): 2054 - 2060. [Abstract] [Full Text] [PDF]

				K. S. Moulton, E. Heller, M. A. Konerding, E. Flynn, W. Palinski, and J. Folkman Angiogenesis Inhibitors Endostatin or TNP-470 Reduce Intimal Neovascularization and Plaque Growth in Apolipoprotein E–Deficient Mice Circulation, April 6, 1999; 99(13): 1726 - 1732. [Abstract] [Full Text] [PDF]

				J.-M. Li and G. Brooks Cell cycle regulatory molecules (cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors) and the cardiovascular system; potential targets for therapy? Eur. Heart J., March 2, 1999; 20(6): 406 - 420. [PDF]

				J Abe, J Deguchi, Y Takuwa, K Hara, Y Ikari, T Tamura, M Ohno, and K Kurokawa Tyrosine phosphorylation of platelet derived growth factor beta  receptors in coronary artery lesions: implications for vascular remodelling after directional coronary atherectomy and unstable angina pectoris Heart, April 1, 1998; 79(4): 400 - 406. [Abstract] [Full Text]

				N. Sin, L. Meng, M. Q. W. Wang, J. J. Wen, W. G. Bornmann, and C. M. Crews The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2 PNAS, June 10, 1997; 94(12): 6099 - 6103. [Abstract] [Full Text] [PDF]

				H. Koyama, Y. Nishizawa, M. Hosoi, S. Fukumoto, K. Kogawa, A. Shioi, and H. Morii The Fumagillin Analogue TNP-470 Inhibits DNA Synthesis of Vascular Smooth Muscle Cells Stimulated by Platelet-Derived Growth Factor and Insulin-like Growth Factor-I: Possible Involvement of Cyclin-Dependent Kinase 2 Circ. Res., October 1, 1996; 79(4): 757 - 764. [Abstract] [Full Text]

				J.-i. Abe, M. Kusuhara, R. J. Ulevitch, B. C. Berk, and J.-D. Lee Big Mitogen-activated Protein Kinase 1(BMK1) Is a Redox-sensitive Kinase J. Biol. Chem., July 12, 1996; 271(28): 16586 - 16590. [Abstract] [Full Text] [PDF]

				K. R. Dover and A. W. Valley Review : Angiogenesis: A new target for antineoplastic therapy Journal of Oncology Pharmacy Practice, January 1, 1996; 2(1): 43 - 60. [Abstract] [PDF]